The goals of this project are to detect and accurately describe menstrually-related mood disorders, explore their pathophysiology and response to pharmacological and environmental manipulation, and to document the relationship between reproductive endocrine change and disorders of mood as a way of further investigating the neurobiology of psychiatric illness. In the past year we have identified: 1) the efficacy of the GnRH analogue (Lupron) in a group of 20 patients with premenstrual syndrome; 2) a differential susceptibility to the mood destabilizing effects of gonadal steroids in patients with a history of premenstrual syndrome compared with controls; 3) preliminary evidence of the absence of a mood destabilizing effect of placebo in the hormone replacement phase of the Lupron protocol; 4) elimination of Wisconsin Card Sort-stimulated activation of regional cerebral blood flow by Lupron, with restoration of normal activation by estrogen or progesterone; 5) blunted m-CPP-stimulated cortisol secretion in the luteal phase and ACTH secretion in both menstrual cycle phases in women with PMS compared with controls; 6) absence of effect of Lupron or steroid replacement on immune response to immune stimulation with recall antigen; 7) lack of reversal of efficacy of fluoxetine by tryptophan depletion in five patients with PMS; 8) increased concentration of Gi and ADP ribosylation in ten controls during estrogen replacement compared with the agonadal state; 9) preliminary evidence of enhanced memory performance during progesterone replacement relative to estrogen replacement; 10) preliminary evidence of the stability of the pattern of symptoms of PMS across multiple menstrual cycles.